At least 10% of the total joint replacements performed annually in the U.S. are revision surgeries, with particle-induced osteolysis and implant loosening as the major indication. There are currently two critical, interrelated barriers to addressing this clinical problem, which affects tens of thousands of people and is predicted to create a major economic burden within 15 years: (i) lack of ability to detect disease early and (ii inability to arrest disease progression or to treat established osteolysis non-surgically. The proximate cause of osteolysis is elevated bone resorption and depressed bone formation, the consequence of a failure cascade initiated by particulate debris shed from the implants. Diagnosis usually depends upon radiographic signs and/or patient-reported pain, both of which occur relatively late in the disease process. Our two central hypotheses are that (i) biomarkers can be identified and used to diagnose osteolysis early in the disease process and (ii) intervention with pharmacological agents that promote bone formation can delay or even reverse particle-induced peri-implant osteolysis and implant loosening. These hypotheses are supported by our recent data showing that several biomarkers, including cathepsin K, are strong candidates for early diagnosis and our study showing that sclerostin antibody is an effective preventive measure. We plan to identify and validate multiple biomarkers for early diagnosis of particle-induced peri-implant osteolysis in our rat model (Aim 1), determine how early in pathogenesis that intervention must be initiated to prevent loss of implant fixation and determine if it is possible to rescue failed fixation in the rat model (Aim 2), and identify biomarkers for erly diagnosis, using an existing 18 year longitudinal repository of body fluids from total hip replacement patients at Rush (Aim 3). Biomarker validation will be accomplished by showing strong predictive ability and by correlating marker levels with pathogenic processes. The study will use proteomics to discover novel candidate markers, which may reveal novel mechanistic pathways. We will test the ability of two bone- building agents (sclerostin antibody and parathyroid hormone) and one anti-resorptive agent (alendronate) to affect peri-implant bone resorption and bone formation and, thereby, prevent or reverse osteolysis. If successful, we will be able to identify peri-implant osteolysis much earlier than is currently possible and will know how early in disease progression that pharmacological intervention must be initiated for successful treatment. We expect the project to lead to future clinical trials in total joint replacement patients to treat particle-induced peri-implant osteolysis non-surgically.